PROJECT SUMMARY Our broad goal is to contribute to a molecular understanding of neurodegenerative processes, such as prion propagation and clearance. We propose to achieve this goal by determining the structures of aggregation-related complexes, including Hsp70-CHIP-tau complex, TREM2 complexes, and 0N4R tau, at near-atomic resolution. In addition, we propose to characterize the native cellular environment of TREM2, thus bridging the gap between atomic-resolution complex models and the cellular scale. The target complexes have been largely refractive to traditional structural biology approaches. Therefore, we will apply integrative structure determination based on sparse, noisy, and ambiguous data largely produced by the consortium, using a variety of different experimental methods, including electron microscopy, solid-state nuclear magnetic resonance spectroscopy, chemical cross- linking with mass spectrometry, soft X-ray tomography, and many others. Structural models will be produced by satisfying all the data simultaneously, using our Integrative Modeling Platform (IMP) software. The models will be used to rationalize the existing experimental data and propose new experiments, such as assessing the phenotypes of relevant point mutations.